German Cancer Research Center: A
protein that influences the epigenetic characteristics of tumor cells is
directly linked to the grade of malignancy of prostate cancer. This key
discovery has been made by a team of scientists from the German Cancer
Research Center (DKFZ), the University of Zurich, Hamburg-Eppendorf
University Hospital, Heidelberg University, and other institutes in a
study of 7,700 samples of tumor tissue. The detection of this biomarker
may serve as an indicator of the likelihood that the disease may take an
aggressive course, and may thus be helpful in choosing an appropriate
treatment. The study was part of the “Early Onset Prostate Cancer”
project, supported by the Federal Ministry of Education and Research
(BMBF) as part of the International Cancer Genome Consortium (ICGC).
When cancer is diagnosed, the grade of its malignancy is a
central concern for both patients and their physicians. This value is
used to determine how intensively and how radically the cancer must be
treated. Particularly in the case of prostate cancer, the disease can
take widely varying courses in different patients. Therefore, cancer
researchers have been looking for measurable, reliable biomarkers that
give clues about the aggressiveness of a tumor in order to choose an
appropriate therapy.
In many types of cancer, alterations in a
tumor’s genetic material indicate how dangerous the cancer is. Prostate
cancer, however, exhibits far fewer of these mutations than other cancer
types. “We have therefore suspected that prostate cancer is driven
primarily by alterations in epigenetic characteristics, that is,
chemical changes in the genetic material that do not affect the sequence
of DNA building blocks,” says Prof. Christoph Plass from the German
Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), who is
one of the project leaders in the current publication.
For a long time, the means by which epigenetic patterns in the DNA of
cancer cells undergo changes have remained a mystery. Scientists have
discovered specific cellular proteins that can have a major influence on
such patterns. A network of researchers from the German Cancer Research
Center (DKFZ), the University of Zurich, Hamburg-Eppendorf University
Hospital, Heidelberg University, and other institutes have been
searching for regulatory proteins that change the epigenetic
characteristics of prostate cancer cells and may thus have an impact on
the course of the disease.
In a first step, the scientists searched databases containing
molecular information on a large number of prostate cancer cases. Using
these data, they investigated whether a particular, known epigenetic
regulatory protein is expressed in tumor cells at significantly higher
or lower levels than in healthy cells from the same patient.
The researchers found the most obvious differences in the expression
of a protein called BAZ2A. “The normal known function of this protein is
to suppress factories that produce cellular proteins and thus affect
the viability of cells,” says Prof. Roland Eils, who leads a research
group at both the DKFZ and at Heidelberg University. “But when we turned
off BAZ2A in the cell lines of metastasizing prostate cancer, their
growth was paradoxically slowed.” Further studies showed that higher
levels of BAZ2A increased specific malignant properties of prostate
cancer cells, including their mobility and capacity to invade
surrounding tissue.
A detailed molecular analysis of prostate cancer cells showed that
the overproduction of BAZ2A led to alterations in epigenetic patterns
which then inhibited the activity of a number of cancer-suppressing
genes. The scientists therefore suspected that the overexpression of
BAZ2A might have a direct impact on the malignancy of prostate cancer
and thus serve as a predictor for the course of the disease.
The team investigated this hypothesis using nearly 7,700 tissue
samples obtained from prostate cancer patients. They discovered that the
higher the BAZ2A levels in the tissue were, the more advanced the tumor
was at the time of diagnosis, the more frequently it had already spread
and formed metastases, and the higher patients’ PSA levels were.
“BAZ2A seems to have a direct influence on the aggressiveness of
prostate cancer,” Plass says. “This suggests that levels of BAZ2A
expression may serve as a valuable predictor of disease progression. Of
course, this still needs to be clinically confirmed. Particularly in
patients whose other clinical results indicate a medium risk, BAZ2A
expression may provide important clues for the actual chances of
recurrence. This would help physicians and patients choose the most
promising treatment.
The study is part of the International Cancer Genome Consortium
(ICGC). Collaborators in the project “Early Onset Prostate Cancer” are
the Martini-Klinik and Hamburg-Eppendorf University Hospital, EMBL,
DKFZ, the National Center for Tumor Diseases (NCT) Heidelberg, and the
Max Planck Institute for Molecular Genetics in Berlin. The project
coordinators are Prof. Christoph Plass from the DKFZ and Prof. Guido
Sauter from Hamburg-Eppendorf University Hospital. The Federal Ministry
of Education and Research (BMBF) has provided funds of €7.5 million for
the project.
Lei Gu, Sandra C Frommel, Christopher C Oakes, Ronald Simon,
Katharina Grupp, Cristina Y Gerig, Dominik Bär, Mark D Robinson,
Constance Baer, Melanie Weiss, Zuguang Gu, Matthieu Schapira, Ruprecht
Kuner, Holger Sültmann, Maurizio Provenzano, ICGC Project on Early Onset
Prostate Cancer, Marie-Laure Yaspo, Benedikt Brors, Jan Korbel,
Thorsten Schlomm, Guido Sauter, Roland Eils, Christoph Plass und
Raffaella Santoro: BAZ2A (TIP5) is involved in epigenetic alterations in
prostate cancer and its overexpression predicts disease recurrence.
Nature Genetics 2014, DOI: 10.1038/ng.3165